Steroids of the 19-norpregnane series



United States Patent STEROIDS OF THE 19-NORPREGNANE SERIES Josef Fried, Princeton, and Mariano A. Guiducci, Edison,

NJ., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed. Aug. 4, 1961', Ser. No. 129,234

12 Claims. (Cl. 260-23955) This invention relates to, and has for its objects the provisions of new physiologically active steroids, methods for preparing the same, and intermediates useful in such preparations.

The final products of this invention are steroids which are 16,17-acetal and ketal derivatives of l'6u,l7ix-dihydroxy-19-norpregnene-3,20-dione steroids, and include steroids of the general formulae and cyclic lower alkyl; or together with the carbon, to-which they are joined P and Q is a monocyclic cycloalkyl or.

monocyclic heterocyclic radical.

The final products of this invention are physiologically-active substances which possess progestational activity and hence can be used in lieu of known pr-ogestational agents, such as progesterone, in the treatment of habitual abortion. For this purpose, they canbeadministered inthe same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. The compounds of this invention can also be administered perorally in the form of tablets. Moreover, it has surprisingly been found that the compounds of this invention are many times more active than are the corresponding 19-methylated derivatives.

The compounds of this invention can bev prepared. by

reducing a compound of the. formula C no o:tt

wherein R (in either the alpha or beta position) is as hereinbefore defined; R is lower alkyl (preferably methyl); P' is hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, or monocyclic cycloalkyl lower alkyl; Q islower alkyl, halo lower alkyl, monocyclic cycloalkyl or monocyclic cycloalkyl lower alkyl; or. together with the carbon to which they are joinedP' and Q isamonocyclic cycloalkyl, to yield new intermediates: of. thisinven-- tion of the general formulal HOCH wherein R, R, P and Q are as hereinbefore defined.

Suitable starting materials for the process of this invention can be prepared as described in our application, Serial No. 129,233, filed on even date herewith, now US. Patent No. 3,077,471, and include the 16,17-cyclic acetals and ketals of l9-nor-3-(lower alkoxy)-l,3,5 (10)-pregnatriene-l6u,17a,20;8-triols, such as 19-nor-3-methoxyl,3,5(10)-pregnatriene-1-6bt,l7a,20,8-triol; and l9-nor-3- (lower alkoxy)-6- (lower alkyl)-1',3,5 10) -pregnatriene- 16oc,17ot,20 3-ifi018, such as 19-nor-3-methoxy-6tat-methyl- 1,3,5(l0)-pregnatriene-l6ot,17a,20,B-triol and 19 nor 3- methoxy 16B methyl 1,3,5 (10) pregnatriene 16oz, 17a,20,8-triol; with aldehydes and ketones, such as the lower alkanals of at least two carbon atoms, the di(lower alkyl)ketones, the cycloalkanones, the cycloalkyl lower alkanals, the. cycloalkyl lower alkanones, the dicyclo. alkyl ketones, the halo-lower alkanals, and the halo-lower alkanones.

The reduction is preferably carried out in liquid; ammonia using an alkali metal, such. as lithiurn,.as the reducing agent. I

The enol ether formed is. then hydrolyzed. The nature of the product formed will" depend on the conditions of the hydrolysis. Thus, if a mineral acid (e.g., dilute sulfuric acid) is used as the nene of the following formula is formed:

HO-CH wherein R, P and Q' are as here-inbefore defined. These compounds are new intermediates of this invention and have progestational activity per se.

If, however, the hydrolysis is carried out by use of an organic carboxylic acid (e.g. oxalic acid), then a 5(10)- pregnene of the following formula is formed:

wherein R, P and Q are as hereinbefore defined. These compounds are also new intermediates of this invention and possess progestational activity.

The 20/3-hydroxy derivatives formed are then oxidized, as by treatment with a hexavalent chromium compound (e.g., chromium trioxide) to yield the corresponding 20- keto derivatives of thefollowing formulae respectively:

(I) H: (i=0 hydrolyzing agent, a 4-pregby treatment with 10% aqueous potassium carbonate in methanol to yield the free 16,17-dihydroxysteroid derivatives. These free 16,17-dihydroxy steroids are new intermediates of this invention which are of the formula (1:0 ---0H Ii Ion wherein R is as hereinbefore defined.

These free 16,17-dihydroxy steroids can then be reacted with an aldehyde or ketone of the formula wherein P and Q are as hereinbefore defined. The reaction is preferably carried out by treating a suspension or solution of the dihydroxy steroid in the aldehyde or ketone (or an organic solvent and the aldehyde or ketone, if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluenesulfonic acid, hydrochloric acid, etc.), neutralizing the acid and recovering the acetal or ketal derivative formed.

Suitable aldehyde and ketone reactants include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; I di(lower alkyl)-ketones, such as acetone, diethylketone,

dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone,

cyclohexanone, suberone, and cyclodexanone; cycloalkyl (lower alkanals), such as cyclopropylcarboxaldehyde, cyclobutylcarboxaldehyde, cyclopentylcarboxaldehyde, cyclohexylcarboxaldehyde, cycloheptylcarboxaldehyde, cyclooctylcarboxaldehyde, cyclopropylacetaldehyde, cyclobutylacetaldehyde, cyclopentylacetaldehyde, cyclohexylacetaldehyde, fl-cyclopentylpropionaldehyde, 'y-cyclohexylbutyraldehyde, and 3-cyclopropylcaproaldehyde; cycloalkyl(lower alkanones), such as .cyclopropyl methyl ketone,

cyclobutyl ethyl ketone, I cyclopentyl propyl ketone, cyclopentylmethyl methyl ketone, cyclohexylrnethyl ethyl ketone, cyclopentylethyl ethyl ketone, cyclopropylpropyl methyl ketone, cyclohexyl n-pentyl ketone, cyclohexyl methyl ketone, and

' cyclooctyl methyl ketone;

dicycloalkyl ketones, such as dicyclopropyl ketone,

dicyclobutyl ketone,

dicyclopentyl ketone,

dicyclohexyl ketone, cyclopentyl cyclohexyl ketone, cyclopropylmethyl cyclopropyl ketone, 2-cyclobutylethyl cyclopropyl ketone, 3-cyclopentylmethyl cyclopentyl ketone, S-cyclohexylhexyl cyclohexyl ketone,

di(cyclopentylmethyl) ketone,

cyclohexylmethyl cyclopentyl ketone, and

di(4-cyclohexylpentyl) ketone;

cycloalkyl monocyclic aromatic ketones, such as cyclopropyl phenyl ketone,

cyclohexyl p-chlorophenyl ketone,

cyclopentyl o-methoxyphenyl ketone,

cyclopentyl o,p-dihydroxyphenyl ketone,

cyclohexyl m-tolyl ketone,

cyclopropyl p-ethylphenyl ketone,

cyclopropyl p-nitrophenyl ketone, and

cyclohexyl p-acetamidophenyl ketone;

cycloalkyl (lower alkyl) monocyclic aromatic ketones,

such as cyclopentylmethyl phenyl ketone;

cycloalkyl monocyclic aromatic (lower alkyl) ketones,

such as cyclopentyl benzyl ketone,

cyclohexyl phenethyl ketone, and

cyclobutyl benzyl ketone;

cycloalkyl (lower alkyl) monocyclic aromatic (lower alkyl) ketones, such as cyclopentylmethyl benzyl ketones;

cycloalkyl monocyclic heterocyclic ketones, such as cyclopentyl Z-furyl ketone,

cyclohexyl 2-thienyl ketone, and

cyclopropyl 2-pyndinyl ketone;

cycloalkyl (lower alkyl) monocyclic heterocyclic ketones,

such as cyclopentylmethyl 2-piperidinyl ketone,

cyclohexylethyl 2-morpholinyl ketone and cyclopropyl Z-thienyl ketone;

cycloalkyl monocyclic heterocyclic (lower alkyl) ketones,

such as cyclopentyl thenyl ketone,

cyclohexyl furfuryl ketone and cyclopropyl 2-piperidinylmethyl ketone;

halo-lower alkanals, such as chloral hydrate,

trifluoroacetaldehyde hemiacetal, and

heptafiuorobutanal ethyl hemiacetal;

halo-lower alkanones, such as 1,1,1-trifluoroacetone;

monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde,

halobenzaldehydes e. g. p-chlorobenzaldehyde and pfluorobenzaldehyde) lower alkoxybenzaldehydes e. g. o-anisaldehyde),

d-i( lower alkoxy)benzaldehydes (e.g. vertraldehyde),

hydroxybenzaldehydes (e.g. salicylaldehyde),

dihydroxybenzaldehydes (e.g. resorcyaldehyde) lower alkyl benzaldehydes (e. g. m-tolualdehyde and pethylbenzalehyde) di(lower alkyl) benzaldehydes (e.g. o,p-dimethylbenzaldehyde) nitrobenzaldehydes, a'cylamidobenzaldehydes (e.g. N-acetylanthranilaldehyde), and

cyanobenzaldehydes;

monocyclic carboxylic aromatic lower allranals, such as phenylacetaldehyde,

e-phenylpropionaldehyde,

B-phenylpropionaldehyde,

*y-phenylbutyraldehyde, and

aromati'cally-substituted halo lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof;

monocyclic heterocyclic aldehydes, such as picolinaldehydes,

cfurfural,

thiophene carbonals, and

halo, lower alkoxy, hydroxy, lower alkyl, nitro, and

cyano derivatives thereof;

monocyclic heterocyclic lower alkanals,

monocyclic carbocyclic aromatic ketones, such as acetophenone,

propiophenone,

butyrophenone,

balerophenone,

isocapropheuone,

halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone),

(lower alkoxy) phenyl lower alkyl ke'tones (e.g. p-anisyl methyl ketone) di(lower alkoxy)phenyl lower alkyl ketones,

hydroxy-phenyl lower alkyl ketones,

dihydroxyphenyl lower alkyl ketones (e.g. resace'tophenone),

(lower alkyl) phenyl lower alkyl ketones (e.g. methyl ptolyl ketone),

di(loweralkyl)-phenyl lower alkyl ketones (o,p-xylyl methyl ketone),

nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone) acylamidophenyl lower alkyl ketones (e.g. acetyl anilines), and

cyanophenyl lower alkyl ketones;

benzophenone, and mono or bis substituted halo,

lower alkoxy, hydroxy, lower alkyl nit-no, acylamido and cyano derivatives thereof;

monocyclic carbocyclic aromatic lower alkano'nes, such as l-phenyl-B-butanone and 1-phenyl-4-pentanone, and

aromatically substituted derivatives thereof;

monocyclic heterocyclic ketones, such as Z-acetylfuran,

Z-benzoylfuran,

Z-acetyl-thiophene and alloxan; and

monocyclic heterocyclic lower alkanones.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 19-n0r-3-meth0xy-2,5 (10 -pregnadiene-1 6 0a,] 7a- ZOB-triol 16ml 7 oc-acetonide To a solution of 235 mg. of l9-nor-3-methoXy-1,3,- 5(l0)-pregnatriene-l6a, l7a,20p-triol 16a,17a-acetonide in 50 ml. of anhydrous ether and ml. of liquid ammonia is added 240 mg. of lithium wire in small pieces. After stirring at room temperature for 1 hour, 2 m1. of methanol is added dropwise over a 5 to 10 minute period, and the ammonia is allowed to evaporate. Water is then added and the mixture extracted with chloroform. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent removed in vacuo. Crystallization of the crude residue (260 mg.) from methanol yields about 190 mg. of crystalline needles, M.P. about 148-150", which upon recrystallization from chloroform-methanol give the analytically pure enol ether with the following properties: M.P. about 157-158"; [a] -]160 (c, 1.1 in chlf.)

M13? 2.87, 5.88 and 5.98 ,1:

no selective UV. absorption. g Y

Ailalysis.-Cal0d. for C H O (388): C, 74.19; H, 9.34; OCH 7.98. Found: C, 74.29; H, 9.42; 'OCHg, 8.15.

EXAMPLE 2 Following the procedure of Example 1 but substituting an equivalent amount of the 16a,l7a-monofluoroacetone derivative of 19 -nor-3-methoXy-1,3,5(10)-pregnatriene- 1602,170c,20B-tfi01 for the acetonide, the 16a,17a-m0110- fluoroacetone derivative of l9-nor-3-rnethoxy-2,5(10)- pregnadiene-l6a,17u,20fl-triol is obtained.

7 7 EXAMPLE 3 160a,] 7a-dicyclopropylketone derivative of 19-nor-3-memethoxy-2,5:(10) -pregnadiene 16a, 17u,20)3zri0l Following the procedure of Example 1 but substituting an equivalent amount of the 16u,17a-dicyclopr-opyl ketone derivative of l9-nor 3-met hoxy l,3,5(l) pregnatriene- 1-6a,'17a-20fi-trio1 for the acetonide, the 160Lj170L-diCYC10- propyl ketone derivative of 19-nor-3-methoxy- 2,5(10)- pregnadiene-16a,17a,'20fi-triol is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifluoroacer tonide derivative and the heptafluorobutanol derivative of 19 nor-3-methoxy-1,3,5*(10)-pregnatriene 16a,17u,20,8- triol, yield the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifluoroacetonide derivative and the heptafluorobutanal derivative of 19- n-or-3-methoxy-2,'5 10) -pregnadiene- 16a, l7u,20 8-triol.

EXAMPLE 4 6a-methyl-19-n0r-3-meth0xy-2,5 (10)-pregnadienel6a,17a,20B-tri0l 16a,17ot-6tcet0nide Following the procedure of Example 1 but substituting an aquivalen-t amount of 60a methyl l9-nor-3-methoxy- 1,3,5 10) -pregnatriene-l6e, l7ct,20 8-triol l6a,l7a-acetonide for the acetonide, 6ot-methyl 19 nor 3 methoxy- 2,5:(10)-pregnadiene-16u,17a,20/3-triol 16cc, 1 7otacetonide is obtained.

EXAMPLE 6,8-methyl-19-nor-3-methoxy-2,5 (1 0 -pregnadiene- 160t,170t,20fi-lfi0l 160a,] 7a-acet0nide "Following the procedure of Example '1 but substituting an equivalent amount of 6fl-methyl-19-nor 3 methoxyide for the acetonide, 6/3-methyl-19-n0r-3-methoxy-2, 5( l0)-pregnaidene-16u,17,2OB-triol 16a,17a-acetonide is obtained.

EXAMPLE 6 To a refluxing solution of 190 mg. of 19-nor-3-methoxy- 2,5(l0)-pregnaidiene-l6a,17u,20,B-triol 16a,l7a-acetonide in 20 m1. of methanol is added 0.60 ml. of an aqueous 8% sulfuric acid solution (w./v.) and the solution is maintained at reflux for 30 minutes. The cooled solution is diluted with water and concentrated in vacuo until most of the methanol is removed, whereupon a heavy precipitate forms. The latter is filtered, washed with water and dried in vacuo. Recrystallization from acetonehexane gives about 95 mg. of crystalline needles M.P. about 232-237. The analytically pure product has the following properties: M.P. about 238240; [a] +30 (c, 1.0 in chlf.);

A 2.86, 2.93, 5.97 and 6.18

max.

Analysis.-Calcd. for C23H34O4 374 c, 73.76; H, 9.15. Found: C, 73.67; H, 9.03.

EXAMPLE 7 8 EXAMPLE 8 a,] 7 a-dicyclopropyl ketone derivative of 19-n0r-4- pregnene-]6a,1 7a,20fl-tri0l-3-0ne EXAMPLE 9 Following the procedure of Example 6 but substituting an equivalent amount of 6a-methy1-19-nor-3-methoxy- 2,5 (10) -pregnadienel6a,17x,20 3-triol l6e,17a-acetonide for the acetonide, 6a-methyl-19-nor-4-pregnene-16 x,17a, ZOfi-triol-S-one 16a,l7ot-acetonide is obtained.

EXAMPLE 1O Following the procedure of Example 6 but substituting an equivalent amount of 6/3-methyl-19-nor-3-methoxy- 2,5 10)-pregnadiene-l6a,17a,20/3-triol l6ot,17ot-acet0nide for the acetonide, 6,8-methyl-19-nor-4-pregnene-16u,l7a, 20,8-triol-3-one 16a,17a-acetonide is obtained.

EXAMPLE 11 19-nor-5(10) -pregnene-16a,17a,20-tri0'l-3-0n=e 16a,1 7aacetonide To a solution of 17.5 mg. of 3-methoxy-19-nor2,5(10)- pregnadiene-l6a,17a,20-trio1 l6a,17a-acetonide in 4.5 ml. of methanol is added 0.9 ml. of a solution containing 230 mg. of oxalic acid in 3 ml. of water. The reaction mixture is stirred at room temperature, poured into ice-water, and extracted with chloroform. The combined chloroform extracts are washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.

EXAMPLE 12 Following the procedure of Example 11 but substituting an equivalent amount of the 16a,17a-monofluoroa'cetone derivative of 19-nor-3-methoxy-2,5(l0)-pregnadiene 16a,17a-20B-triol for the acetonide, the 16oc,17oc-II1OI10- fluoroacetone derivative of 19-nor-5(10)-pregnene-16u, 17a,20/3-triol-3-one is obtained.

EXAMPLE 13 1 6 u,] 7 u-dicyclopropyl ketone derivative 0 19-n0r-5 (1 0) pregnene-16u,1 7 u,20B-tri0l-3 -on'e Following the procedure of Example 11 but substitut ing an equivalent amount of the l6oc,l7ocdicyclopropyl ketone derivative of 19-nor-3-methoxy-2,5(10)-pregnadiene-l6u,l7a,20fi-triol for the acetonide, the 16a,17adicyclopropyl ketone derivative of 19-nor-5(10)-pregnene- 16a,17a,20,B-triol-3-one is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative and the heptafluorobutanal derivative of 19 nor 3-methoxy-2,5 (l0) -pregnadiene-16a,1'7a,20,8-

triol, yield the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifluoroacetonide derivative and the heptafluorobutanal derivative of 19- nor-( -pregnene-16a,17a,20,B-triol-3-one.

EXAMPLE 14 Following the procedure of Example 11 but substituting an equivalent amount of Got-methyl-19-nor-3-methoxy- 2,5 10)-pregnadiene-16a,17u,20B-triol 16a,17u-acetonide for the acetonide, 6a-methyl-19-nor-5 10)-pregnene-16oz, 170:,20B-t1i0l-3-01'16 16a,17a-acetonide is obtained.

EXAMPLE Following the procedure of Example 11 but substituting an equivalent amount of 6,6-methyl-19-nor-3-methoxy-2,5 (10)-pregnadiene-l6a,17a,20,B-triol 16a,1'7 x-acetonide for the acetonide, 6B-methyl-19-nor-5(10)-pregnene-l6oc,17u, 205-triol-3-one l6u,17a-acetonide is obtained.

EXAMPLE 16 19-n0r-1 6 0a,] 7 a-dihydroxyprogesterone 1 6 a,1 7a-acet0nid e To a solution of 34 mg. of 19-nor-4-pregnene-16a,17a, 8-triol-3-one 160:,l7oc-8C6t01'1id in 8 ml. of acetonide is added slowly with stirring 0.8 ml. of a solution containing 16 mg. of chromium trioxide and 26 mg. of sulfuric acid in 90% aqueous acetone. After stirring for a total of 15 minutes methanol is added to reduce the excess chromium trioxide. The solution is diluted with water and concentrated in vacuo to remove most of the acetone and methanol. The residual suspension is filtered, washed with water and the precipitate dried in vacuo. Crystallization from acetone-hexane yields about mg. of needles, M.P. about 224-227, which on recrystallization from acetonehexane gives the analytically pure 19-nor-16u,17u-dihydroxyprogesterone acetonide of the following properties: M.P. about 228-230" +81 (c, 1.1 in chlf.);

Nu iol 5.85, 5.95 and 6.16 a k312i. 2 ma (e=16,250)

Analysis.Calcd. for C H O (372): C, 74.16; H, 8.66. Found: C, 74.04; H, 8.54.

EXAMPLE 17' J 9-n0r-5 (1 0) -pregnene-16a,] 7 a-diol-3,20-di0ne 160g] 7 a-acetonide EXAMPLE 18 1 6 0a,] 7 a-monofluoroacetone derivative of 19-n0r- 1 6 05,1 7ot-dihydr0xypr0gester0ne Following the procedure of Example 16 but substituting an equivalent amount of the 16u,17a-monofluoroacetone derivative of 19-nor-4-pregnene-16a,17u,20,6-triol-3-0ne for the acetonide, the 16a,17a-monofiuoroacetone derivative of 19-nor-16a,17a-dihydroxyprogesterone is obtained.

. 10 EXAMPLE 19 16u,17u-dicycl0pr0pyl ketone derivative" of 19-n0r- 1 6 04,1 7a-dihydr0xy progesterone Following the procedure of Example 16 but substituting an equivalent amount of the 16u,17b-dicyc1opropyl ketone derivative of 19-nor-4-pregnene-16a,17a,20,B-triol-3-one for the acetonide, the 16a,17ot-dicyclopropyl ketone derivative of 19-nor-l6a,17a-dihydroxyprogesterone is obtained.

Simlarly, the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifluoroacetonide derivative and the heptafluorobutanal derivative of 19-nor-4=pregnene-1-6a,17a,20B-triol-3-one, yield the; methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative and the heptafluorobutanal derivative of l9-I10r16oz,17ocdihydroxyprog'esterone.

EXAMPLE 20 6u-methy l-19n0r-16a,1 7 a-dihydroxyprogesferone 1604,] 7 a-acetonide Following the procedure of Example 16 but substitut ing an equivalent amount of 6a-methyl-19-nor-4-pregnene-l6u,17a-20fl-triol-3-one 16a,17a-acetonide for the acetonide, 6a-methyl-19-nor-16a,17a-dihydroxypr0gesterone 16a,17a-acetonide is obtained.

EXAMPLE 21 6fi-methyl-19-n0r-16aJ 7 a-dihydroxyprogeslerone 16a,1 7 tat-acetonide Following the procedure of Example 16 but substituting an equivalent amount of 6fi-methyl-19-nor-4-pregnene-l6ix,17a,20,8-tri0l-3-one 16a,17a-acet0nide for the acetonide, 6,8-methyl-19-nor-16a,17u-dihydroxyprogesterone 16oc,17oc-3C6OI1ide is obtained.

EXAMPLE 22 a,] 7 a-m onofluoroacetone derivative 0 19-n0r-5 (10) pregnene 16a,1 7 u-di0l-3,20-d z'one Following the procedure of Example 17 but substituting an equivalent amount of the 16a,17am0110fl110108.- tone derivative of 19-nor-5(10)-pregnene-16a,17u,20fitrio1-3-0ne for the acetonide, the 16a,17a-I11OI10flUOIOaC6- tone derivative of 19-nor-5(10)-pregnene-16a,17oc-diol- 3,20-dione is obtained.

EXAMPLE 23 I6a,17a-dicycl0pr0pyl ketone derivative of 19-n0r 5 (1 0 -pregnene-16oc,1 7 a-diOl-3,20-di0ll Following the procedure of Example 17 but substituting an equivalent amount of the l6a,17 x-dicyclopropyl ketone derivative of 19-nor-5(10)-pregnene 16a,17a,20fitriol-3-one for the acetonide, the l6a,17a-dicyclopropyl ketone derivative of 19-nor-5(10)-pregnene-16u,17a-diol- 3,20-dione is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative and the heptafluorobutanal derivative of 19 nor 5(10) pregnene 16a,17a,20/3 triol- 3-one, yield the methylisobutyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative and the heptafluorobutanal derivative of 19-nor-5 10) -pregnene-1 60:,17a-dl01-3 ,20-dione.

EXAMPLE 24 6 a-methyZ-J 9-n0r-5 (10) -pregnene-16a,17a-di0I-3,20- dione ]6a,17a-acet0nide Following the procedure of Example 17 but substituting an equivalent amount of 6a-methyl-19-nor-5(10)- pregnene-l6a-17a,205-triol-3one 16a,17u-acetonide for the acetonide, 6a-methyl-19-nor-5(10)-pregnene-16a,17adiol-3,20-dione 16a,17a-acetonide is obtained.

1 1 EXAMPLE 2s 6,6-methyl-19-n0r-5 (1 -pregnene-16a,1 7a-di0l-3,20- 16a,1 7a-aeelonide Followingthe procedure of Example 17 but substituting an equivalent amount of 6B-methyl-19-nor-5(10)- pregnene-l6a,17a,20[3-triol-3-one 16a,17a-acetonide for the acetonide, 6 fl-methyl-19-nor-5 10) -pregnene-16a,17a diol-3,20-dione 16a,17a-acetonide is obtained.

7 EXAMPLE 26 19-n0r-1 6 0a,] 7 a-dihydroxyprogeszerone A solution of 830 mg. of 19-nor-16a,17a-dihydroxyprogesterone 16a,17oc-3.C't0nid6 in 25 m1. of 88% formic acid is allowed to remain at 42 for 22 hours. At the end of that period the formic acid is removed completely in vacuo and the crude residue is dissolved in 83 ml. of oxygen-free methanol. To this solution is added under nitrogen 16.6 ml. of an oxygen-free 10% potassium carbonate solution and the mixture is allowed to remain at room temperature under nitrogen for 30 minutes. 1.7 m1. of glacial acetic acid is then added followed by 100 ml. of water. Upon removal of the bulk of the methanol in vacuo crystallization of the resulting 19-nor-16a,17adihydroxyprogesterone ensues. The crystalline precipitate is filtered, dried and recrystallized from acetone-hexane. The pure material melts at about 182-184;

EXAMPLE 27 6a-methyl-19-nor-1 6 a,] 7 a-dihydroxyprogesterone Following the procedure of Example 26 but substituting an equivalent amount of 6a-methyl-19-nor-16a,17adihydroxypr'ogesterone 16a,17aacetonide for the autohide, 6a-methyl-19-nor-16a,17a-dihydroxyprogesterone is obtained.

EXAMPLE 28 6/8-methyl-19-n0r-16aJ 7 a-dihydroxy progesterone Following the procedure of Example 26 but substituting an equivalent amount of 6,8-methyl-19-nor-16a,17adihy-droxyproges-terone l6a,17aacetonide for (the acetoe nide, 6,6-methyl-19-nor-16a,:17a-di-hyd noxyprogesterone is obtained.

EXAMPLE 29 Acetophenone derivative of 19-n0r-16a,17adihydroxyprogesterone A suspension of 100 mg. of 19-nor-16a,17a-dihydroxyprogesterone in ml. of redistilled acetophenone and .025 ml. of 70% perchloric acid stirred at room temperature for 1 /2 hours. The resulting solution is neutralized with sodium bicarbonate solution and after the addition of chloroform, the layers are separated and the organic phase washed with water. Removal of the chloroform and acetophenone in high vacuum leaves a residue (95 mg), which on recrystallization from acetone-hexane gives the pure acetophenone derivative of 19-nor-l6a,17adihydroxyprogesterone.

EXAMPLE 30 Benzaldehyde derivatives of 19-n0r-16a,1 7 adihydroxyprogesterone Following the procedure of Example 29 but substituting an equivalent amount of benzaldehyde for the acetophenone, the isomeric benzaldehyde derivatives of 19- nor-16a,17a-dihydroxyprogesterone are obtained which are separated by chromatography on alumina.

EXAMPLE 31 Furfaral derivatives of 19-n0r-16a,1 7adihy droxy progesterone Following the procedure of Example 29 but substituting an equivalent amount of furfural for the acetophenone,

. '12 the isomeric furfural derivatives of 19-nor-16a,l7a-dihydroxyprogesterone are obtained, which are separated by alumina chromatography.

EXAMPLE 32 Thiopene-Z-earb0xaldehyde derivatives of 19a-nor- 1 6a,] 7a-dihydroxyprogesterone Following the procedure of Example 29 but substituting an equivalent amount of thiophene-Z-carboxaldehyde for the acetophenone, the thiophene-2-carboxaldehyde derivatives of 19-nor-16a,17a-dihydroxyprogesterone are obtained, which are separated by alumina chromatography.

EXAMPLE 33 2 -acetylfaran derivative of l9-n0r-16a,17a-

dihydroxyprogesterone Following the procedure of Example 29 but substituting an equivalent amount of Z-acetylfuran for the acetophenone, the 2-acetylfuran derivative of 19-nor-16a,17adihydroxyprogesterone is obtained.

EXAMPLE 34 Z-acetylthiophene derivative 0]" 19-n0r-16a,17adihydroxyprogesterone Following the procedure of Example 29 but substituting an equivalent amount of 2-acetylthiophene for the acetophenone, the Z-acetylthiophene derivative of 19-nor- 16a,17a-dihydroxyprogesterone is obtained.

Similarly, by substituting any other aldehyde or ketone for the acetophenone in the procedure of Example 29, all other acetals and ketals of this invention can be prepared.

EXAMPLE 3s Acetophenone derivative of 6a-methyl-19-n0r-16a,17adihy droxyprogesterone Following the procedure of Example 29 but substituting an equivalent amountof 6a-methanol-19-nor- 16a,17a dihydroxyprogesterone for the 19-nor-16al7adihydroxyprogesterone, the acetophenone derivative of 6a-methyl-19-nor-16a,17a-dihy-droxyprogesterone is obtained. V

I EXAMPLE 36 Acetopherz one derivative of 6,8-methyl-19-nOr-16a,17adihydroxyprogesterone and wherein R is selected from the group consisting of hydrogen and lower alkyl; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic andmonocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group carbon 1110 which they are joined P and Q is monocyclic heterocyclic.

2. A compound of the formula wherein R is selected from the group consisting of hydrogen and lower alkyl; R is lower alkyl; P is selected from the group consisting hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl and monocyclic cycloalkyl lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl and monocyclic cycloalkyl lower alkyl; and together with the carbon to which they are joined P and Q is monocyclic cycloalkyl.

3. 19-nor-3-methoxy 2,5 pregnadiene16a,17a,- ZOfl-triol 16a,17aacetonide.

4. A compound selected from the group consisting of steroids of the formulae wherein R is selected from the group consisting of hydrogen and lower alkyl; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl and monocyclic cycloalkyl lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl and monocyclic cycloalkyl lower alkyl; and together with the carbon to which they are joined P and Q is monocyclic cycloalkyl.

5. 19-nor-4-pregnene-16a,l7u,20 3-triol-3-one :,1704- acetonide.

6. 19-nor 5 (10) pregnene-16a,17a,20,B-tri0l-3-one 1606,1706-8C6t01'1id6.

7. 19-nor 16oc,l7oz dihydroxyprogesterone 16a,17aacetonide.

8. 19-nor 5 (10) pregnene-16a,l7a-diol-3,20 dione 160:,17uc-3C6t0l1id6.

9. 19-nor 1600,1711 dihydroxyprogesterone 16a,17aacetophenonide.

10. A compound of the formula wherein R is selected from the group consisting of hydrogen and lower alkyl.

11. 19-nor-16a,17a-dihydroxyprogesterone.

12. 16a,17a-isopropylidenedioxy 60c methyl-l9-norprogesterone.

References Cited by the Examiner UNITED STATES PATENTS 2,941,997 6/ 1960 Fried 260-23955 3,002,968 10/ 1961 Bernstein et a1. 260239.55

OTHER REFERENCES Cooley et al., J.C.S., 1955, pp. 4373-76. Fieser et al., Steroids, Reinhold Publishing Corp., June 25, 1959, (pp. 589 and 620 relied on).

Fried et al., Chemistry and Industry, Apr. 15, 1961, pp. 466-67.

Mills et al., J.A.C.S., vol. 82 (1960), pp. 3399-04. Tullner et al., C.A., vol. 51, p. 8283(e), 1957.

LEWIS GOTTS, Primary Examiner.

M. LIEBERMAN, IRVING MARCUS, G. E. LANDE,

Assistant Examiners. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE FORMULA 